The invention relates to targeting methods for therapy; particularly for targeting genes, proteins, pharmaceuticals, or other compounds to the central nervous system.
The capabilities to introduce a particular foreign or native gene sequence into a mammal and to control the expression of that gene are of substantial value in the fields of medical and biological research. Such capabilities provide a means for studying gene regulation and for designing a therapeutic basis for the treatment of disease.
In addition to introducing the gene into mammals, providing expression of the gene at the site of interest remains a challenge. Methods have been developed to deliver DNA to target cells by capitalizing on endogenous cellular pathways of macromolecular transport. In this regard, gene transfer has been accomplished via the receptor-mediated endocytosis pathway employing molecular conjugate vectors.
Inherited diseases of the central nervous system (CNS) pose a therapeutic challenge. Pharmacological approaches do not significantly alter the course of many of these diseases as such approaches fail to correct the underlying genetic deficit. New approaches, relying on the transfer of genetic material have been advocated. However, current methodologies used for gene therapy are limited in their usefulness with regard to treating CNS disorders.
A particular challenge to delivery of many substances to the CNS, including substances for gene therapy, is posed by the selective permeability of the Blood Brain Barrier (BBB). BBB is formed by cerebral endothelial cells and limits the passage of substances from blood into CNS cells, particularly large and/or highly polar molecules.
Under certain pathological conditions, including CNS lesions caused by infections, inflammatory conditions, neoplasms, and ischemia, the BBB becomes more permeable relative to normal conditions. This change in permeability has been used in designing a method for delivering drugs to the CNS in conjunction with substances that neutralize the excess drug circulating outside the BBB to minimize systemic side effects (U.S. Pat. No. 5,124,149).
Other approaches for delivering substances to the CNS have included circumventing the BBB by intrathecal administration into cerebrospinal fluid by direct injection or surgical implant, direct injection and infusion into CNS tissue (Ommaya et al. (1984) Cancer Drug Delivery 1(2):169-178; U.S. Pat. No. 5,222,982; Bobo et al. (1994) Proc. Natl. Acad. Sci. USA 91:2076-2080); altering the blood brain barrier by osmotic disruption through use of chemical agents (U.S. Pat. No. 4,866,042), use of carriers capable of crossing the BBB (U.S. Pat. No. 5,716,614), and tagging with molecules capable of binding specific CNS receptors (U.S. Pat. No. 5,527,527).
Direct administration of therapeutic substances to the CNS, particularly the brain, is rare and associated with high safety risk. Additionally, local administration of gene therapy vectors or transplantation of donor cells is likely to only treat the immediate area of the injection site. Effective therapy with these methods requires multiple injections and carry the safety risks associated with intrusion into the CNS, disease transmission and the use of immunosuppressive drugs.
Current approaches to gene therapy in inherited CNS disorders are limited in practicality by the mode of administration or the capacity of the vector used for gene transfer. Therefore, methods are needed for targeting specific compositions to CNS cells.
Compositions and methods for targeting genes, proteins, pharmaceuticals, or other compounds to the central nervous system (CNS) are provided. The compositions comprise peptide sequences which bind CNS tissue, in vivo, with high specificity.
The compositions are useful in therapy methods for the treatment of CNS disorders, and delivery of a wide variety of compounds to the CNS, including nucleotides, proteins and small molecule pharmaceuticals.